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Entinostat

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https://www.readbyqxmd.com/read/28340413/design-synthesis-and-biological-evaluation-of-novel-coumarin-based-benzamides-as-potent-histone-deacetylase-inhibitors-and-anticancer-agents
#1
Tooba Abdizadeh, Mohammad Reza Kalani, Khalil Abnous, Zahra Tayarani-Najaran, Bibi Zahra Khashyarmanesh, Rahman Abdizadeh, Razieh Ghodsi, Farzin Hadizadeh
Histone deacetylases (HDACs) are attractive therapeutic targets for the treatment of cancer and other diseases. It has four classes (I-IV), among them especially class I isozyme are involved in promoting tumor cells proliferation, angiogenesis, differentiation, invasion and metastasis and also viable targets for cancer therapeutics. A novel series of coumarin-based benzamides was designed and synthesized as HDAC inhibitors. The cytotoxic activity of the synthesized compounds (8a-u) was evaluated against six human cancer cell lines including HCT116, A2780, MCF7, PC3, HL60 and A549 and a single normal cell line (Huvec)...
March 18, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28338101/the-histone-deacetylase-inhibitor-valproic-acid-inhibits-nkg2d-expression-in-natural-killer-cells-through-suppression-of-stat3-and-hdac3
#2
Lulu Ni, Lixin Wang, Chao Yao, Zhongya Ni, Fei Liu, Chenyuan Gong, Xiaowen Zhu, Xuewei Yan, Stephanie S Watowich, Dean A Lee, Shiguo Zhu
NKG2D is a major activating receptor of NK cells and plays a critical role in tumor immunosurveillance. NKG2D expression in NK cells is inhibited by the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and enhanced by the narrow-spectrum HDAC inhibitor entinostat. We previously demonstrated that entinostat enhanced NKG2D transcription by increasing acetylation of Histones H3 and H4. However, the mechanism by which VPA reduces NKG2D expression in NK cells is not known. We have also shown that NKG2D transcription is regulated by STAT3 phosphorylation...
March 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28326839/entinostat-a-promising-treatment-option-for-patients-with-advanced-breast-cancer
#3
Roisin M Connolly, Michelle A Rudek, Richard Piekarz
Entinostat is a synthetic benzamide derivative histone deacetylase (HDAC) inhibitor, which potently and selectively inhibits class I and IV HDAC enzymes. This action promotes histone hyperacetylation and transcriptional activation of specific genes, with subsequent inhibition of cell proliferation, terminal differentiation and apoptosis. This oral HDAC inhibitor has been evaluated in Phase I and II trials in patients with advanced malignancies, and is in general well tolerated. Entinostat does not currently have regulatory approval for clinical use; however promising preclinical and clinical data exist in hormone-resistant breast cancer...
March 9, 2017: Future Oncology
https://www.readbyqxmd.com/read/28315487/xpln-is-modulated-by-hdac-inhibitors-and-negatively-regulates-sparc-expression-by-targeting-mtorc2-in-human-lung-fibroblasts
#4
Koichiro Kamio, Arata Azuma, Jiro Usuki, Kuniko Matsuda, Minoru Inomata, Nobuhiko Nishijima, Shioto Itakura, Hiroki Hayashi, Takeru Kashiwada, Nariaki Kokuho, Kenichiro Atsumi, Tomoyoshi Yamaguchi, Kazue Fujita, Yoshinobu Saito, Shinji Abe, Kaoru Kubota, Akihiko Gemma
Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that participates in the assembly and turnover of the extracellular matrix, whose expression is regulated by transforming growth factor (TGF)-β1 through activation of mammalian target of rapamycin complex 2 (mTORC2). Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. However, whether XPLN modulates SPARC expression remains unknown...
March 14, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28186961/combination-epigenetic-therapy-in-metastatic-colorectal-cancer-mcrc-with-subcutaneous-5-azacitidine-and-entinostat-a-phase-2-consortium-stand-up-2-cancer-study
#5
Nilofer S Azad, Anthony El-Khoueiry, Jun Yin, Ann L Oberg, Patrick Flynn, Douglas Adkins, Anup Sharma, Daniel J Weisenberger, Thomas Brown, Prakriti Medvari, Peter A Jones, Hariharan Easwaran, Ihab Kamel, Nathan Bahary, George Kim, Joel Picus, Henry C Pitot, Charles Erlichman, Ross Donehower, Hui Shen, Peter W Laird, Richard Piekarz, Stephen Baylin, Nita Ahuja
PURPOSE: Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies. EXPERIMENTAL DESIGN: We conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 75 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10...
February 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28077797/repression-of-fyn-related-kinase-in-breast-cancer-cells-is-associated-with-promoter-site-specific-cpg-methylation
#6
Edward T Bagu, Sayem Miah, Chenlu Dai, Travis Spriggs, Yetunde Ogunbolude, Erika Beaton, Michelle Sanders, Raghuveera K Goel, Keith Bonham, Kiven E Lukong
The triple-negative breast cancer subtype is highly aggressive and has no defined therapeutic target. Fyn-related kinase (FRK) is a non-receptor tyrosine kinase, reported to be downregulated in breast cancer and gliomas, where it is suggested to have tumor suppressor activity. We examined the expression profile of FRK in a panel of 40 breast cancer cells representing all the major subtypes, as well as in 4 non-malignant mammary epithelial cell lines. We found that FRK expression was significantly repressed in a proportion of basal B breast cancer cell lines...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28052439/an-hdac-inhibitor-entinostat-ms-275-partially-prevents-delayed-cranial-suture-closure-in-heterozygous-runx2-null-mice
#7
H S Bae, W J Yoon, Y D Cho, R Islam, H R Shin, B S Kim, J M Lim, M S Seo, S A Cho, K Y Choi, S H Baek, H G Kim, K M Woo, J H Baek, Y S Lee, H M Ryoo
Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder caused by mutations in RUNX2, coding a key transcription factor of early osteogenesis. CCD patients suffer from the developmental defects in cranial bones. Despite numerous investigations and clinical approaches, no therapeutic strategy has been suggested to prevent CCD. Here, we show that fetal administration of Entinostat/MS-275, a class I histone deacetylase (HDAC)-specific inhibitor, partially prevents delayed closure of cranial sutures in Runx2(+/-) mice strain of C57BL/6J by two mechanisms: (1) post-translational acetylation of Runx2 protein, which stabilized the protein and activated its transcriptional activity; and (2) epigenetic regulation of Runx2 and other bone marker genes...
January 4, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28011471/histone-deacetylase-inhibitors-an-attractive-therapeutic-strategy-against-breast-cancer
#8
REVIEW
Christos Damaskos, Serena Valsami, Michael Kontos, Eleftherios Spartalis, Theodoros Kalampokas, Emmanouil Kalampokas, Antonios Athanasiou, Demetrios Moris, Afrodite Daskalopoulou, Spyridon Davakis, Gerasimos Tsourouflis, Konstantinos Kontzoglou, Despina Perrea, Nikolaos Nikiteas, Dimitrios Dimitroulis
With a lifetime risk estimated to be one in eight in industrialized countries, breast cancer is the most frequent type of cancer among women worldwide. Patients are often treated with anti-estrogens, but it is common that some tumors develop resistance to therapy. The causation and progression of cancer is controlled by epigenetic processes, so there is an ongoing interest in research into mechanisms, genes and signaling pathways associating carcinogenesis with epigenetic modulation of gene expression. Given the fact that histone deacetylases (HDACs) have a great impact on chromatin remodeling and epigenetics, their inhibitors have become a very interesting field of research...
2017: Anticancer Research
https://www.readbyqxmd.com/read/27999738/the-interplay-of-epigenetic-therapy-and-immunity-in-locally-recurrent-or-metastatic-estrogen-receptor-positive-breast-cancer-correlative-analysis-of-encore-301-a-randomized-placebo-controlled-phase-ii-trial-of-exemestane-with-or-without-entinostat
#9
Yusuke Tomita, Min-Jung Lee, Sunmin Lee, Saori Tomita, Saranya Chumsri, Scott Cruickshank, Peter Ordentlich, Jane B Trepel
Entinostat, a class I-selective histone deacetylase inhibitor, has shown promising activity in ENCORE 301, a randomized, placebo-controlled, phase II trial of exemestane with or without entinostat in women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on a nonsteroidal aromatase inhibitor. ENCORE 301 showed an 8.3-mo improvement in median overall survival among patients who received entinostat. We investigated the impact of entinostat on immune subsets with CD40, HLA-DR, and immune checkpoint receptor expression analyses in 34 patient blood samples from ENCORE 301...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27979916/combination-epigenetic-therapy-in-advanced-breast-cancer-with-5-azacitidine-and-entinostat-a-phase-ii-national-cancer-institute-stand-up-to-cancer-study
#10
Roisin Connolly, Huili Li, Rachel C Jankowitz, Zhe Zhang, Michelle A Rudek, Stacie C Jeter, Shannon Slater, Penny Powers, Antonio C Wolff, John H Fetting, Adam M Brufsky, Richard Piekarz, Nita Ahuja, Peter W Laird, Hui Shen, Daniel J Weisenberger, Leslie Cope, James G Herman, George Somlo, Agustin Garcia, Peter A Jones, Stephen B Baylin, Nancy E Davidson, Cynthia Zahnow, Vered Stearns
PURPOSE: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to re-expression of genes encoding important therapeutic targets including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine (AZA) and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Patients received AZA 40 mg/m2 (days 1-5, 8-10) and entinostat 7 mg (days 3,10) of 28 day cycle...
December 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27892955/erratum-the-histone-deacetylase-inhibiting-drug-entinostat-induces-lipid-accumulation-in-differentiated-heparg-cells
#11
Abigail D G Nunn, Tullio Scopigno, Natalia Pediconi, Massimo Levrero, Henning Hagman, Juris Kiskis, Annika Enejder
No abstract text is available yet for this article.
November 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27797970/molecular-pathways-maintaining-mapk-inhibitor-sensitivity-by-targeting-nonmutational-tolerance
#12
Michael P Smith, Claudia Wellbrock
Targeting hyperactive MAPK signaling has proven to be an effective treatment for a variety of different cancers. Responses to the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitors trametinib and cobimetinib are, however, transient, and complete remission is rarely observed; rather, outgrowth of resistant clones within progressed tumors appears inevitable. These resistant tumors display great heterogeneity, which poses a major challenge to any salvage therapy. Recent focus has, therefore, been on the early dynamics of inhibitor response during tumor regression...
December 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27792246/inhibition-of-histone-deacetylases-in-melanoma-a-perspective-from-bench-to-bedside
#13
REVIEW
Eva Hornig, Markus V Heppt, Saskia A Graf, Thomas Ruzicka, Carola Berking
Histone deacetylases (HDACs) are critically involved in epigenetic gene regulation through alterations of the chromatin status of DNA. Aberrant expression, dysregulation of their enzymatic activity or imbalances between HDACs and histone acetyltransferases are likely involved in the development and progression of cancer. Pharmacologic inhibition of HDACs shows potent antitumor activity in a panel of malignancies such as colon or gastric cancer and multiple myeloma. In this review, we summarize the current knowledge of HDACs in melanoma and evaluate the application of HDAC inhibition from an experimental and clinical perspective...
November 2016: Experimental Dermatology
https://www.readbyqxmd.com/read/27765934/patient-derived-mouse-models-of-cancer-need-to-be-orthotopic-in-order-to-evaluate-targeted-anti-metastatic-therapy
#14
Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Nan Zhang, Takashi Murakami, Takashi Chishima, Kuniya Tanaka, Yasushi Ichikawa, Michael Bouvet, Itaru Endo, Robert M Hoffman
Patient-derived xenograft (PDX) mouse models of cancer are emerging as an important component of personalized precision cancer therapy. However, most models currently offered to patients have their tumors subcutaneously-transplanted in immunodeficient mice, which rarely metastasize. In contrast, orthotopic-transplant patient-derived models, termed patient-derived orthotopic xenografts (PDOX), usually metastasize as in the patient. We demonstrate in the present report why orthotopic models are so important for the patient, since primary and metastatic tumors developed in an orthotopic model can have differential chemosensitivity, not detectable in standard subcutaneous tumor models...
November 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27761810/assessment-of-hdaci-induced-protein-cleavage-by-caspases
#15
Fabian Treude, Tobias Gladbach, Jacqueline Plaster, Jörg Hartkamp
Aberrant histone deacetylase (HDAC) activity often correlates with neoplastic transformation and inhibition of HDACs by small molecules has emerged as a promising strategy to treat hematological malignancies in particular. Treatment with HDAC inhibitors (HDACis) often prompts tumor cells to undergo apoptosis, thereby causing a caspase-dependent cleavage of target proteins. An unexpectedly large number of proteins are in vivo caspase substrates and defining caspase-mediated substrate specificity is a major challenge...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27705911/targeting-sall4-by-entinostat-in-lung-cancer
#16
Kol Jia Yong, Ailing Li, Wen-Bin Ou, Clarice Kit Yee Hong, Wenxiu Zhao, Fei Wang, Hiro Tatetsu, Benedict Yan, Lihua Qi, Jonathan A Fletcher, Henry Yang, Ross Soo, Daniel G Tenen, Li Chai
The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling of SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Connectivity Map analysis revealed the HDAC inhibitor entinostat as a potential drug in treating SALL4-expressing cancers, and this was confirmed in 17 lung cancer cell lines...
September 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27633343/entinostat-up-regulates-the-camp-gene-encoding-ll-37-via-activation-of-stat3-and-hif-1%C3%AE-transcription-factors
#17
Erica Miraglia, Frank Nylén, Katarina Johansson, Elias Arnér, Marcus Cebula, Susan Farmand, Håkan Ottosson, Roger Strömberg, Gudmundur H Gudmundsson, Birgitta Agerberth, Peter Bergman
Bacterial resistance against classical antibiotics is a growing problem and the development of new antibiotics is limited. Thus, novel alternatives to antibiotics are warranted. Antimicrobial peptides (AMPs) are effector molecules of innate immunity that can be induced by several compounds, including vitamin D and phenyl-butyrate (PBA). Utilizing a luciferase based assay, we recently discovered that the histone deacetylase inhibitor Entinostat is a potent inducer of the CAMP gene encoding the human cathelicidin LL-37...
September 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27619199/differentiation-therapy-in-poor-risk-myeloid-malignancies-results-of-companion-phase-ii-studies
#18
Kelly J Norsworthy, Eunpi Cho, Jyoti Arora, Jeanne Kowalski, Hua-Ling Tsai, Erica Warlick, Margaret Showel, Keith W Pratz, Lesley A Sutherland, Steven D Gore, Anna Ferguson, Sarah Sakoian, Jackie Greer, Igor Espinoza-Delgado, Richard J Jones, William H Matsui, B Douglas Smith
Pre-clinical data in non-M3 AML supports the use of differentiation therapy, but clinical activity has been limited. Myeloid growth factors can enhance anti-leukemic activity of differentiating agents in vitro. We conducted companion phase II trials investigating sargramostim (GM-CSF) 125μg/m(2)/day plus 1) bexarotene (BEX) 300mg/m(2)/day or 2) entinostat (ENT) 4-8mg/m(2)/week in patients with MDS or relapsed/refractory AML. Primary endpoints were response after at least two treatment cycles and toxicity. 26 patients enrolled on the BEX trial had a median of 2 prior treatments and 24 enrolled on the ENT trial had a median of 1...
October 2016: Leukemia Research
https://www.readbyqxmd.com/read/27576506/histone-deacetylase-inhibitors-induce-proteolysis-of-activated-cdc42-associated-kinase-1-in-leukemic-cells
#19
Nisintha Mahendrarajah, Ramin Paulus, Oliver H Krämer
PURPOSE: Activated CDC42-associated kinase-1 (ACK1/TNK2) and epigenetic regulators of the histone deacetylase (HDAC) family regulate the proliferation and survival of leukemic cells. 18 HDACs fall into four classes (I-IV). We tested the impact of clinically relevant histone deacetylase inhibitors (HDACi) on ACK1 and if such drugs combine favorably with the therapeutically used ACK1 inhibitor Dasatinib. METHODS: We applied the broad-range HDACi Panobinostat/LBH589 and the class I HDAC-specific inhibitor Entinostat/MS-275 to various acute and chronic myeloid leukemia cells (AML/CML)...
November 2016: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/27551531/an-epithelial-marker-promoter-induction-screen-identifies-histone-deacetylase-inhibitors-to-restore-epithelial-differentiation-and-abolishes-anchorage-independence-growth-in-cancers
#20
H M Tang, K T Kuay, P F Koh, M Asad, T Z Tan, V Y Chung, S C Lee, J P Thiery, Ry-J Huang
Epithelial-mesenchymal transition (EMT), a crucial mechanism in development, mediates aggressiveness during carcinoma progression and therapeutic refractoriness. The reversibility of EMT makes it an attractive strategy in designing novel therapeutic approaches. Therefore, drug discovery pipelines for EMT reversal are in need to discover emerging classes of compounds. Here, we outline a pre-clinical drug screening platform for EMT reversal that consists of three phases of drug discovery and validation. From the Phase 1 epithelial marker promoter induction (EpI) screen on a library consisting of compounds being approved by Food and Drug Administration (FDA), Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi), is identified to exert EMT reversal effects by restoring the expression of an epithelial marker, E-cadherin...
2016: Cell Death Discovery
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